555 research outputs found

    Focusing Qualitative Simulation Using Temporal Logic: Theoretical Foundations

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    this paper took place while the author was visiting the Qualitative Reasoning Group at the Dept. of Computer Sciences of the University of Texas at Austin. G. Brajnik and D.J. Clancy / Focusing qualitative simulation 2 formation about the trajectory of a variable or relationships between the trajectories of interconnected variables. Such information allows the modeler to restrict the simulation to a region of the state space and to specify time--varying input variables. The Temporally Constrained Qsim (TeQsim, pronounced tek'sim) algorithm combines the expressive power of these two paradigms by interleaving temporal logic model checking with qualitative simulation. Temporal logic is used to specify qualitative and quantitative trajectory information that is incorporated into the simulation to constrain and refine the resulting behaviors. Qualitative simulation constructs a set of possible behaviors consistent with a model of a dynamical system represented by a qualitative differential equation (QDE). The Qsi

    Gastroentological investigations

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    In this fourth article in the Concepts in Anatomy series, Anne-Marie Ramsay joins John Clancy and Andrew McVicar in examining the upper and lower gastrointestinal tract and identifies some common homeostatic imbalances. Diagnostic tests for detecting abnormalities are described, highlighting the importance of the nurse's role in caring for the patient throughout these procedures. This series is based on Physiology and Anatomy, a homeostatic approach, 2nd ed, John Clancy and Andrew McVicar (eds), Edward Arnold, London, 1995, currently in print. </jats:p

    The guanine nucleotide exchange factor Gea1 rescues an isoform-specific 14-3-3 phenotype

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    14-3-3 proteins are abundant modulators of cellular processes, in particular signal transduction. They function by binding to a broad spectrum of client proteins, thus affecting client protein localisation or function[1]Gardino 2011 [1]Morrison 2009 [2][2]. Animals and plants express 14-3-3 proteins encoded by several genes, which has made it difficult to study their unique rather than shared functions. The yeast Saccharomyces cerevisiae possesses only two highly homologous 14-3-3 genes, BMH1 and BMH2. Using this model system we now uncover novel aspects of functional specificity between the two yeast 14-3-3s. We show that bmh1 but not bmh2 cells display an altered morphology of the endomembrane system and specific trafficking defects under glucose starvation. This but not a second phenotype specific to the bmh1 strain, that is, the accumulation of glycogen, was rescued by overexpression of the nucleotide exchange factor Gea1, suggesting a role for Bmh1 in Gea1’s function or regulation

    Bat3 promotes the membrane integration of tail-anchored proteins

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    The membrane integration of tail-anchored proteins at the endoplasmic reticulum (ER) is post-translational, with different tail-anchored proteins exploiting distinct cytosolic factors. For example, mammalian TRC40 has a well-defined role during delivery of tail-anchored proteins to the ER. Although its Saccharomyces cerevisiae equivalent, Get3, is known to function in concert with at least four other components, Get1, Get2, Get4 and Get5 (Mdy2), the role of additional mammalian proteins during tail-anchored protein biogenesis is unclear. To this end, we analysed the cytosolic binding partners of Sec61β, a well-defined substrate of TRC40, and identified Bat3 as a previously unknown interacting partner. Depletion of Bat3 inhibits the membrane integration of Sec61β, but not of a second, TRC40-independent, tail-anchored protein, cytochrome b5. Thus, Bat3 influences the in vitro membrane integration of tail-anchored proteins using the TRC40 pathway. When expressed in Saccharomyces cerevisiae lacking a functional GET pathway for tail-anchored protein biogenesis, Bat3 associates with the resulting cytosolic pool of non-targeted chains and diverts it to the nucleus. This Bat3-mediated mislocalisation is not dependent upon Sgt2, a recently identified component of the yeast GET pathway, and we propose that Bat3 either modulates the TRC40 pathway in higher eukaryotes or provides an alternative fate for newly synthesised tail-anchored proteins. © 2010. Published by The Company of Biologists Ltd

    delta-COP contains a helix C-terminal to its longin domain key to COPI dynamics and function.

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    Membrane recruitment of coatomer and formation of coat protein I (COPI)-coated vesicles is crucial to homeostasis in the early secretory pathway. The conformational dynamics of COPI during cargo capture and vesicle formation is incompletely understood. By scanning the length of delta-COP via functional complementation in yeast, we dissect the domains of the delta-COP subunit. We show that the mu-homology domain is dispensable for COPI function in the early secretory pathway, whereas the N-terminal longin domain is essential. We map a previously uncharacterized helix, C-terminal to the longin domain, that is specifically required for the retrieval of HDEL-bearing endoplasmic reticulum-luminal residents. It is positionally analogous to an unstructured linker that becomes helical and membrane-facing in the open form of the AP2 clathrin adaptor complex. Based on the amphipathic nature of the critical helix it may probe the membrane for lipid packing defects or mediate interaction with cargo and thus contribute to stabilizing membrane-associated coatomer

    WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane.

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    Tail-Anchored (TA) proteins are inserted into the endoplasmic reticulum (ER) membrane of yeast cells via the posttranslational Guided Entry of Tail-Anchored protein (GET) pathway. The key component of this targeting machinery is the ATPase Get3 that docks to the ER membrane by interacting with a receptor complex formed by the proteins Get1 and Get2. A conserved pathway is present in higher eukaryotes and is mediated by TRC40, homolog of Get3, and the recently identified membrane receptors WRB and CAML. Here, we used yeast lacking the GET1 and GET2 genes and substituted them with WRB and CAML. This rescued the growth phenotypes of the GET receptor mutant. We demonstrate that WRB and CAML efficiently recruit Get3 to the ER membrane and promote the targeting of the TA proteins in vivo. Our results show that the membrane spanning segments of CAML are essential to create a functional receptor with WRB and to ensure TA protein membrane insertion. Finally, we determined the binding parameters of TRC40 to the WRB/CAML receptor. We conclude that together, WRB and CAML are not only necessary but also sufficient to create a functional membrane receptor complex for TRC40. The yeast complementation assay can be used to further dissect the structure-function relationship of the WRB/CAML heteromultimer in the absence of endogenous receptor proteins

    Fighter wing a guided tour of an Air Force combat wing

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    New York Times bestselling author Tom Clancy takes readers on an inside tour of an Air Force combat wing--the planes, the technology, and the people--capturing the thrill of takeoff, the drama of a dogfight, and the relentless dangers which fighter pilots face every day of their lives. Exclusive photos, diagrams, and illustrations throughout
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